The Specific Aims of the proposal are: 1) To dissect the role of PI3-K in the regulation of signalling protein (MEK and MAPK) activation in hematopoietic cells using constitutively active and dominant negative PI3-K mutants. 2) To biochemically and genetically identify the novel MEK activator in the wortmannin-sensitive, IL-3-inducible MEK activation pathway. 3) To determine the roles of MEK and MAPK and upstream regulators in hematopoietic cell proliferation and survival using transient and long-term proliferation assays. These studies are designed to characterize a discreet wortmannin-sensitive MAPK activation pathway that based on preliminary data may have cell type-specific components. Once identified these components will provide novel signal-transducing targets for pharmacological intervention to block cytokine-dependent proliferation of leukemic and normal myeloid lineage cells.
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| Sutor, S L; Vroman, B T; Armstrong, E A et al. (1999) A phosphatidylinositol 3-kinase-dependent pathway that differentially regulates c-Raf and A-Raf. J Biol Chem 274:7002-10 |
